BCG immunotherapy for bladder cancer triggers systemic and local BCG-specific CD4⁺ Th1 responses

High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with intravesical instillations of Bacillus Calmette-Guérin (BCG), which trigger a local immune response. Improved patient outcomes have been linked to the recruitment of CD4⁺ T helper type 1 (Th1) cells to the bladder. However, specific antigens recognized by the bladder-infiltrating T cells remain largely unknown. In this study, we followed thirty-two patients with NMIBC undergoing BCG immunotherapy. Longitudinal blood and urine samples were collected to investigate the dynamics and characteristics of BCG-specific T cells. We detected pre-existing BCG-specific CD4⁺ T cells in most BCG therapy-naive patients before treatment induction. BCG immunotherapy increased the frequency and memory differentiation of circulating BCG-specific CD4⁺ T cells, which displayed a polyfunctional Th1 phenotype. Importantly, we provide evidence that BCG-specific CD4⁺ Th1 cells can be detected in urine during therapy, suggesting their recruitment to the bladder. This study provides novel biological insights into the cellular mechanisms of BCG-induced immunity in bladder cancer.